CYP4F2 polymorphism as a genetic risk factor for major hemorrhagic complications in Chinese patients on warfarin therapy

Warfarin is a commonly used anticoagulant with a narrow therapeutic range and risk of hemorrhagic complications. After CYP2C9 and VKORC1, CYP4F2 was confirmed as the third principle genetic determinant of warfarin dose variability. CYP4F2 functions as a vitamin K1 (VK1) oxidase, a counterpart to vitamin K oxidize reductase (encoded by VKORC1) in limiting excessive accumulation of VK1 in vitamin K cycle. Genotypes of CYP2C9 and VKORC1 are associate with increased risk of over anticoagulation or bleeding events during warfarin therapy. However, little is known about the influence of CYP4F2. Herein we present the association of CYP4F2 polymorphism and risk of major hemorrhage in Chinese patients on warfarin. HapMap Data (Phase III/Rel#2, Feb09, on NCBI B36 assembly, dbSNP b126) covering 50 kb length centered on CYP4F2 for Chinese was downloaded (http://hapmap.ncbi. nlm.nih.gov/). Haplotype blocks were constructed using Haploview version 4.2 software. The tag SNPs were selected with an LOD score cutoff of 3.0 and r threshold of 0.80. We genotyped eight tag SNPs (rs7251296, rs4808394, rs12610962, rs3093168, rs2074901, rs2018454, rs1558139 and rs3093200) in CYP4F2 using the multiplexed PCR-based SNaPshot system (Applied Biosystems) in 312 Han Chinese patients on warfarin. Three genetic determinants of warfarin dose, CYP2C9*3, VKORC1 -1639 G>A, and CYP4F2 V433M were also genotyped. Among the genotyped 312 patients (mean age, 56.6 ± 16.0 years; 50.6% men) on warfarin with